Imidazo[1,5-a]-quinolinium and imidazo[1,5-a]-pyridinium compounds

ABSTRACT

The synthesis of imidazo[1,2-a]pyridinium, imidazo[1,5-a]pyridinium, pyrrolo[1,2-a]pyrazinium, pyrazolo[1,5-a]pyridinium, imidazo[2,1-a]isoquinolinium and imidazo[5,1-a]isoquinolinium quaternary salts and their use as hypoglycemic agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of application Ser. No. 712,204 as filedAug. 6, 1976, and now U.S. Pat. No. 4,044,015, which in turn is acontinuation-in-part of application Ser. No. 609,914, filed Sept. 3,1975 and now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to fused heterocyclic quaternary salts ashypoglycemic agents, and more particularly to imidazo[1,2-a]pyridinium,imidazo-[1,5-a]pyridinium, pyrrolo[1,2-a]pyrazinium,pyrazolo[1,5-a]pyridinium, imidazo-[2,1-a]isoquinolinium andimidazo[5,1-a]isoquinolinium quaternary salts as orally-effective bloodsugar lowering agents in the treatment of diabetes.

Other than insulin, which is usually administered subcutaneously, themost useful oral medication employed in the treatment of diabetes arethe sulfonylureas, many of which are currently being marketed. Inaddition, biguanides are also employed either alone or in combinationwith sulfonylureas in the treatment of this disease.

Recently, 1-substituted 3-(2-pyrimidinyl)imidazolium salts have beenclaimed in Belgium Pat. No. 743,510 and German patent application No.1,964,282, to be active as hypoglycemic agents. Japanese patentapplication No. 7305899 reports the synthesis of pyridinium-pyrazine andtheir use as lowerers of blood sugar and free fatty acid levels.Wiegand, et. al., J. Med. Chem., 15, 1326 (1972), review and report onthe hypoglycemic activity of a number of azolylpyridinium salts, whileU.S. Pat. No. 3,860,718 teaches the use of imidazo[2,1-b]thiazoliumsalts as blood sugar lowering agents.

2,3,9-Trimethylbenzimidazo[2,1-b]thiazolium iodide has been prepared byde Stevens, et. al., J. Am. Chem. Soc., 79, 5710 (1957),imidazo[2,1-b]-thiazolium by Kondo, et. al., J. Pharm. Soc., Japan, 57,1050 (1937) (C.A. 32, 3398 (1938) and Kickhofen, et. al., Chem. Ber.,88, 1109 (1955) (C.A. 50, 13911 [1956]), and imidazo[1,2-a]quinoliniumsalts by Habermalz, et. al., Chem. Ber., 108, 984 (1975).

Dissertation Abstracts 68-11,711 reports the synthesis ofimidazo-[1,5-a]pyridine methiodide, while Bradsher, et. al., J.Heterocyclic Chem., 2, 331 (1965), reports the preparation of1,2,3-trimethylimidazo[1,2-a]pyridinium bromide,1-methyl-2-phenylimidazo[1,2-a]pyridinium bromide,1-phenyl-2-methylimidazo[1,2-a]pyridinium bromide,1-phenylimidazo[1,2-a]pyridinium perchlorate,1-methylimidazo[1,2-a]pyridinium perchlorate,1-benzyl-2-phenylimidazo[1,2-a]-pyridinium bromide and1-benzyl-2-methylimidazo[1,2-a]pyridinium bromide.

SUMMARY OF THE INVENTION

It has now been discovered that quaternary salts ofimidazo[1,2-a]-pyridine, imidazo[1,5-a]pyridine, pyrrolo[1,2-a]pyrazine,pyrazolo[1,5-a]-pyridine, imidazo[2,1-a]isoquinoline andimidazo[5,1-a]isoquinoline are orally effective hypoglycemic agentsuseful in the reduction of blood sugar levels of diabetics. The firstpreferred group of compounds are those of the formula: ##STR1## where R₁is hydrogen, chloro, methoxy or benzyloxy; R₃ is benzyl,α-naphthylmethyl, β-naphthylmethyl, β-phenethyl or benzyl substituted bychloro, fluoro, dichloro, trifluoromethyl, cyano, methylsulfonyl,dimethylsulfamoyl, carbethoxy, phenyl or methoxy; and X is apharmaceutically acceptable anion.

The broken line shown in the above structure I represents an optionalbond such that the present invention is meant to embrace both the2,3-dihydro-and dehydro- forms of the imidazo[1,2-a]pyridiniumcompounds.

Especially preferred within this first group of compounds are those offormula I wherein R₁ is hydrogen and R₃ is benzyl or substituted benzyl.

The second group of compounds within the scope of the invention arethose of the formula: ##STR2## where R is hydrogen or the carbon andhydrogen atoms completing a fused 6,7-benzo moiety; R₄ is alkyl havingone to three carbon atoms, benzyl or substituted benzyl wherein thesubstituent is chloro or dichloro; R₅ and R₆ are each phenyl orhydrogen, provided that when R₅ and R₆ are both hydrogen, R₄ is benzylor substituted benzyl wherein said substituent is chloro or dichloro;and X is a pharmaceutically acceptable anion. The compound wherein R₅and R₆ are both hydrogen, R₄ is methyl, R is hydrogen and X is iodide,which is reported of unspecified activity in Dissertation Abstracts68-11,711, is devoid of any significant hypoglycemic activity.

Especially preferred within this group are compounds wherein R, R₅ andR₆ are hydrogen. A second especially preferred group are those whereinR₄ is methyl and R₅ is phenyl. A third especially preferred group ofhypoglycemic compounds are those wherein R₄ is methyl and R₆ is phenyl.A final group of especially preferred compounds are those wherein R isthe carbon and hydrogen atoms completing a fused 6,7-benzo moiety and R₅and R₆ are each hydrogen.

The third preferred group of compounds within the scope of the instantinvention are those of the formulae: ##STR3## where R is hydrogen or thecarbon and hydrogen atoms completing a fused 3,4-benzo moiety; Q and Zare each hydrogen or chlorine; and X is a pharmaceutically acceptableanion.

A fourth preferred group of compounds within the scope of the inventionare hypoglycemic agents of the formula: ##STR4## where R₁ is hydrogen,chlorine, methoxy or benzyloxy; R₂ is furfuryl or 8-quinolylmethyl; andX is a pharmaceutically acceptable anion.

A fifth preferred group of compounds within the purview of the presentinvention are congeners of the formula: ##STR5## where Y is chlorine,bromine or methoxy; Z is hydrogen or chlorine and X is apharmaceutically acceptable anion.

In all the aforementioned preferred groups of blood sugar loweringagents, it is preferred that X is chloro, bromo, iodo or sulfate.

Also useful as antidiabetic agents and considered within the scope ofthe present invention are the known compounds,1-benzyl-2-phenylimidazo[1,2-a]pyridinium and1-methyl-2-phenylimidazo[1,2-a]pyridinium salts wherein the anion ofsaid salts are pharmaceutically acceptable ones.

DETAILED DESCRIPTION OF THE INVENTION

The hypoglycemic agents of the present invention are synthesized by thereaction of a suitable halide with the appropriate heterocyclic ringsystem, depicted as follows: ##STR6## wherein R,R₂, R₁, R₃, R₄, R₅, R₆,Q, Y, Z and X are as previously described.

Transformation of the above-mentioned heterocyclic compounds toquaternary salts is effected by reacting with a halide where X ispreferably chloro, bromo or iodo. Said reaction can be conducted betweenequimolar amounts of the two reagents either neat or in the presence ofa suitable reaction-inert solvent. When conducted neat a large excess ofthe halide can be employed, acting under these conditions as both areactant and solvent.

By a reaction-inert solvent is meant one which does not react to anyappreciable degree with the product or reactants under the conditions ofsaid reaction. Solvents suitable for the solublizing of the reactantsleading to the quaternary compounds can be of a varied nature, and caninclude (lower)-alkanols, (lower)alkylnitriles, di(lower)alkyl ketones,cyclic- and di(lower)-alkyl ethers and liquid aromatic hydrocarbons. Thepreferred solvent for this reaction is acetonitrile.

Reaction time is not critical, and depends on temperature, concentrationand inherent reactivity of the reagents. When steam bath temperaturesare employed, completion of the reaction usually requires overnightheating.

The product is isolated by cooling the reaction mixture to inducecrystallization, or initial concentration of the reaction mixturefollowed by cooling and addition of a second solvent to inducecrystallization. Further purification of the final product isfacilitated by trituration or recrystallization from an appropriatesolvent.

As mentioned previously, quaternary salt formation is preferablyeffected wherein X of the alkylating agent is bromo, chloro, or iodo.Following isolation of these salts the nature of the X variable can bealtered by initially treating an aqueous solution of quaternary halidewith an equivalent of silver oxide, followed by separation of theprecipitated silver halide and treatment of the aqueous solution of thequaternary base with at least an equivalent of an appropriate acid HX.

Alternately, the quaternary base can be obtained by passing a solutionof a salt through a basic ion-exchange resin column followed bytreatment of the eluate with the same or a different acid.

In the utilization of the chemotherapeutic activity of those compoundsof the present invention which form quaternary salts, it is preferred,of course, to use pharmaceutically acceptable salts. Althoughwater-insolubility, toxicity, or lack of crystalline nature may makesome particular salt species unsuitable or less desirable for use assuch in a given pharmaceutical application, the water insoluble or toxicsalts can be converted to the corresponding pharmaceutically acceptablequaternary hydroxide by decomposition of the salt as described above, oralternately they can be converted to any desired pharmaceuticallyacceptable quaternary salt.

Examples of pharmaceutically acceptable anions other than the halidesare nitrate, sulfate, phosphate, alkanoates, lactate, citrate, tartrate,succinate and maleate.

The heterocyclic intermediate leading to the quaternary salts of thepresent invention are prepared by known procedures or by hereinafterdescribed methods. The halide intermediates are commercial reagents orare synthesized by procedures either taught in chemical literature orfamiliar to those skilled in the art.

As previously mentioned, the quaternary salts are all readily adapted totherapeutic use as oral hypoglycemic agents in view of their ability tolower blood sugar levels of diabetic subjects. Toward this end, thepreferred compounds are 1-benzylimidazo[1,2-a]pyridinium bromide,1-benzyl-6-chloroimidazo[1,2-a]pyridinium bromide,1-benzyl-8-benzyloxyimidazo[1,2-a]pyridinium,1-benzyl-5-methoxyimidazo[1,2-a]pyridinium bromide,1-benzyl-2,3-dihydroimidazo-[1,2-a]pyridinium bromide,1-benzylimidazo[1,2-a]pyridinium chloride,1-benzylimidazo[1,2-a]pyridinium sulfate,1-(2-chlorobenzyl)imidazo[1,2-a]pyridinium chloride,1-(3-chlorobenzyl)imidazo[1,2-a]pyridinium bromide,1-(4-chlorobenzyl)-imidazo[1,2-a]pyridinium chloride,1-(2-chlorobenzyl)-2,3-dihydroimidazo[1,2-a]-pyridinium chloride,1-(3-chlorobenzyl)-2,3-dihydroimidazo[1,2-a]pyridinium chloride,1-(4-chlorobenzyl)-2,3-dihydroimidazo[1,2-a]pyridinium chloride,1-(4-bromobenzyl)imidazo[1,2-a]pyridinium chloride,1-(2-fluorobenzyl)imidazo[1,2-a]-pyridinium chloride,1-(4-fluorobenzyl)imidazo[1,2-a]pyridinium bromide, 1-(2-bromobenzyl)imidazo[1,2-a]pyridinium bromide,1-(8-quinolylmethyl)imidazo[1,2-a]-pyridinium bromide,1-furfurylimidazo[1,2-a]pyridinium chloride,1-methyl-2-(4-chlorophenyl)imidazo[1,2-a]pyridinium iodide,1-methyl-2-(4-bromophenyl)imidazo-[1,2-a]pyridinium iodide,1-methyl-2-(4-methoxyphenyl)imidazo[1,2-a]pyridinium iodide,2-(2-chlorobenzyl)imidazo[1,5-a]pyridinium chloride,2-benzylimidazo-[1,5-a]pyridinium bromide,1-phenyl-2-methylimidazo[1,5-a]pyridinium iodide,2-methyl-3-phenylimidazo[1,5-a]pyridinium iodide,2-benzylimidazo[1,5-a]quinolinium bromide,2-(2-chlorobenzyl)-imidazo[1,5-a]quinolinium chloride,2-benzylpyrrolo[1,2-a]pyrazinium bromide,1-benzylpyrazolo[1,5-a]pyridinium bromide,1-benzyl-1H-imidazo[2,1-a]isoquinolinium bromide,1-(2-chlorobenzyl)-1H-imidazo[2,1-a]isoquinolinium chloride,2-benzylimidazo[5,1-a]isoquinolinium bromide and2-(2-chlorobenzyl)-imidazo[5,1-a]isoquinolinium chloride.

The quaternary salts, which are useful hypoglycemic agents in mammals,can be administered either as individual therapeutic agents or asmixtures of therapeutic agents. They can be administered alone, but aregenerally administered with a pharmaceutical carrier selected on thebasis of the chosen route of administration and standard pharmaceuticalpractice. For example, they may be combined with variouspharmaceutically acceptable carriers in the form of tablets, capsules,lozenges, troches, hard candies, powders, aqueous suspensions orsolutions, injectable solutions, elixirs, syrups and the like. Suchcarriers include solid diluents or filters, sterile aqueous media andvarious nontoxic organic solvents. Moreover, the bral pharmaceuticalcompositions of this invention may be suitably sweetened and flavored bymeans of various agents of the type commonly used for this purpose.

The particular carrier selected and the proportion of active ingredientto carrier are influenced by the solubility and chemical nature of thetherapeutic compounds, the chosen route of administration and the needsof the standard pharmaceutical practice. For example, where thosecompounds are administered orally in tablet form, excipients such aslactose, sodium citrate, calcium carbonate and dicalcium phosphate maybe used. Various disintegrants such as starch, alginic acids, andcertain complex silicates, together with lubricating agents such asmagnesium stearate, sodium lauryl sulphate and talc, may also be used inproducing tablets for the oral administration of these compounds. Fororal administration in capsule form, high molecular weight polyethyleneglycols are among the preferred materials for use as pharmaceuticallyacceptable carriers. Where aqueous suspensions are to be used for oraladministration, the compounds of this invention may be combined withemulsifying or suspending agents. Diluents such as ethanol, propyleneglycol, glycerine and their combinations may be employed as well asother materials.

For purposes of parenteral administration, solutions or suspensions ofthe instant compounds in sesame or peanut oil or in aqueous propyleneglycol solutions can be employed, as well as sterile aqueous solutionsdescribed hereinafter. These particular solutions are especially suitedfor intramuscular and subcutaneous injection purposes. The aqueoussolutions dissolved in pure distilled water are also useful forintravenous injection purposes provided that their pH is properlyadjusted beforehand. Such isolations should also be suitably buffered,if necessary, and the liquid diluent first rendered isotonic withsufficient saline.

It is necessary that the active ingredient form a proportion of thecomposition such that a suitable dosage form will be obtained.Obviously, several dosage unit forms may be administered at about thesame time. Although compositions with less than 0.005 percent by weightof active ingredient might be used in certain instances, it is preferredto use compositions containing not less than 0.005 percent of the activeingredient; otherwise the amount of carrier becomes excessively large.Activity increases with the concentration of the active ingredient. Thecomposition may contain 10, 50, 75, 95, or an even higher percentage byweight of the active ingredient.

Although the use of the present invention is directed toward thetreatment of mammals in general, the preferred subject is humans. Indetermining an efficacious dose for human therapy, results of animaltesting are frequently extrapolated and a correlation is assumed betweenanimal test behavior and proposed human dosage. When a commerciallyemployed standard is available, the dose level of the clinical candidatein humans is frequently determined by comparison of its performance withthe standard in an animal test. For example, β-phenethylbiguanide isemployed as a standard hypoglycemic agent and is administered to humansat the rate of 50 to 150 mg. daily. It is assumed, then, that ifcompounds of the present invention have activity comparable toβ-phenethylbiguanide in the test assay, that similar doses will providecomparable responses in humans.

Obviously, the physician will ultimately determine the dosage which willbe most suitable for a particular individual, and it will vary with theage, weight and response of the particular patient as well as with thenature and extent of the symptoms and the pharmacodynamiccharacteristics of the particular agent to be administered. Generally,small doses will be administered initially, with a gradual increase inthe dosage until the optimum level is determined. It will often be foundthat when the composition is administered orally, larger quantities ofthe active ingredient will be required to produce the same level asproduced by a small quantity administered parenterally.

Having full regard for the foregoing factors, it is considered that aneffective daily dosage of the compounds of the present invention inhumans of approximately 50 to 600 mg. per day, with a preferred range ofabout 50 to 400 mg. per day in single or divided dose, or at about 0.07to 0.6 mg./kg. of body weight will effectively lower blood sugar levelsin human diabetic subjects. These values are illustrative, and theremay, of course, be individual cases where higher or lower dose rangesare merited.

The following examples are provided solely for the purpose ofillustration and are not to be construed as limitations of thisinvention, many variations of which are possible without departing fromthe spirit or scope thereof.

EXAMPLE 1 1-Benzylimidazo[1,2-a]pyridinium Bromide A.imidazo[1,2-a]pyridine

A mixture of 47 g. of 2-aminopyridine, 120 g. of a 45%chloroacetaldehyde solution in water and 50.4 g. of sodium bicarbonatein 400 ml. of anhydrous ethanol and 100 ml. of water is heated to refluxfor 3 hrs. The reaction mixture is cooled, treated with 900 ml. of waterand extracted with diethyl ether (3×700 ml.). The combined extracts aredried over sodium sulfate and concentrated to a brown oil. Distillationgives 18.8 g. of the desired intermediate as a light yellow oil, b.p.70° C./0.02 mm.

B. 1-benzylimidazo[1,2-a]pyridinium bromide

To 1.77 g. of imidazo[1,2-a]pyridine in 40 ml. of acetonitrile is added3.42 g. of α-bromotoluene, and the resulting mixture heated to refluxovernight. The resulting solution is cooled, and the precipitated solidsfiltered. Recrystallization of the crude product from acetonitrileaffords the pure product as a white solid, 2.33 g., m.p. 169°-171° C.

Anal. Calc'd for C₁₄ H₁₃ N₂ Br: C, 58.2; H, 4.5; N, 9.7. Found: C, 58.1;H, 4.5; N, 9.7.

EXAMPLE 2

Starting with imidazo[1,2-a]pyridine and the appropriate halide, andemploying the procedure of Example 1-B, the following quaternary saltsare prepared in the indicated % yield:

1-(2,6-Dichlorobenzyl)imidazo[1,2-a]pyridinium chloride (69% yield),m.p. 235°-238° C.

Anal. Calc'd for C₁₄ H₁₁ N₂ Cl₃ : C, 53.6; H, 3.5; N, 8.9. Found: C,53.5; H, 3.6; N, 9.1.

1-(2,4-Dichlorobenzyl)imidazo[1,2-a]pyridinium chloride (90% yield),m.p. 207°-213° C.

Anal. Calc'd for C₁₄ H₁₁ N₂ Cl₃ : C, 53.6; H, 3.5; N, 8.9. Found: C,53.4; H, 3.6; N, 9.0.

1-(4-Methoxybenzyl)imidazo[1,2-a]pyridinium chloride (85% yield), m.p.197°-200° C.

Anal. Calc'd for C₁₅ H₁₅ ON₂ Cl: C, 65.6; H, 5.5; N, 10.2. Found: C,65.4; H, 5.5; N, 10.2.

1-(2-Chlorobenzyl)imidazo[1,2-a]pyridinium chloride (62% yield), m.p.212°-215° C.

Anal. Calc'd for C₁₄ H₁₂ N₂ Cl₂ : C, 60.2; H, 4.3; N, 10.0. Found: C,60.2; H, 4.3; N, 10.2.

1-(3-Chlorobenzyl)imidazo[1,2-a]pyridinium bromide (85% yield), m.p.206°-208.5° C.

Anal. Calc'd for C₁₄ H₁₂ N₂ BrCl: C, 51.9; H, 3.7; N, 8.1. Found: C,52.0; H, 3.7; N, 8.1.

1-(4-Chlorobenzyl)imidazo[1,2-a]pyridinium chloride (81% yield), m.p.241°-245° C.

Anal. Calc'd for C₁₄ H₁₂ N₂ Cl₂ : C, 60.2; H, 4.3; N, 10.0. Found: C,60.4; H, 4.3; N, 10.1.

1-(4-Cyanobenzyl)imidazo[1,2-a]pyridinium bromide (80% yield), m.p.216°-218° C.

Anal. Calc'd for C₁₅ H₁₂ N₃ Br: C, 57.3; H, 3.9; N, 13.2. Found: C,57.0; H, 3.8; N, 13.1.

1-(2-Bromobenzyl)imidazo[1,2-a]pyridinium bromide (49% yield), m.p.229°-232° C.

Anal. Calc'd for C₁₄ H₁₂ N₂ Br₂ : C, 45.7; H, 3.3; N, 7.6. Found: C,45.5; H, 3.4; N, 8.7.

1-(4-Bromobenzyl)imidazo[1,2-a]pyridinium chloride (65% yield), m.p.237°-240° C.

Anal. Calc'd for C₁₄ H₁₂ N₂ BrCl: C, 52.0; H, 3.8; N, 8.7. Found: C,52.1; H, 3.8; N, 8.7.

1-(2-Fluorobenzyl)imidazo[1,2-a]pyridinium chloride (33% yield), m.p.194°-197° C.

Anal. Calc'd for C₁₄ H₁₂ N₂ ClF: C, 64.0; H, 4.6; N, 10.7. Found: C,63.6; H, 4.6; N, 10.5.

1-(4-Fluorobenzyl)imidazo[1,2-a]pyridinium bromide (33% yield), m.p.154°-156° C.

Anal. Calc'd for C₁₄ H₁₂ N₂ BrF: C, 54.7; H, 3.9; N, 9.1. Found: C,54.3; H, 4.0; N, 8.9.

1-(3-Trifluoromethylbenzyl)imidazo[1,2-a]pyridinium chloride (43%yield), m.p. 172°-175° C.

Anal. Calc'd for C₁₅ H₁₂ N₂ F₃ Cl.1/2H₂ O: C, 56.4; H, 4.1; N, 8.7.Found: C, 56.0; H, 4.1; N, 8.7.

1-(4-Phenylbenzyl)imidazo[1,2-a]pyridinium bromide (31% yield), m.p.184°-187° C.

Anal. Calc'd for C₂₀ H₁₇ N₂ Br: C, 65.8; H, 4.7; N, 7.6. Found: C, 65.6;H, 4.8; N, 7.6.

1-(4-Methylsulfonylbenzyl)imidazo[1,2-a]pyridinium bromide (76% yield),m.p. 254°-256° C.

Anal. Calc'd for C₁₅ H₁₅ O₂ N₂ SBr: C, 49.1; H, 4.1; N, 7.6. Found: C,49.1; H, 4.2; N, 7.7.

1-(4-Sulfamoylbenzyl)imidazo[1,2-a]pyridinium bromide (54% yield), m.p.252°-255° C.

Anal. Calc'd for C₁₄ H₁₄ O₂ N₃ SBr: C, 45.7; H, 3.8; N, 11.4. Found: C,45.3; H, 3.8; N, 11.2.

1-(4-Carbethoxybenzyl)imidazo[1,2-a]pyridinium bromide (44% yield), m.p.124°-128° C.

Anal. Calc'd for C₁₇ H₁₇ O₂ N₂ Br.1/4H₂ O: C, 55.6; H, 4.9; N, 7.7.Found: C, 55.6; H, 5.1; N, 7.5.

1-(4-Dimethylsulfamoylbenzyl)imidazo[1,2-a]pyridinium bromide (11%yield), m.p. 230°-235° C.

Anal. Calc'd for C₁₆ H₁₈ N₃ O₂ SBr: C, 48.5; H, 4.6; N, 10.6. Found: C,48.4; H, 4.7; N, 10.5.

1-(1-Naphthylmethyl)imidazo[1,2-a]pyridinium chloride (62% yield), m.p.236°-240° C.

Anal. Calc'd for C₁₈ H₁₅ N₂ Cl: C, 73.3; H, 5.1; N, 9.5. Found: C, 73.5;H, 5.4; N, 9.3.

1-(2-Naphthylmethyl)imidazo[1,2-a]pyridinium bromide (58% yield), m.p.172°-176° C.

Anal. Calc'd for C₁₈ H₁₅ N₂ Br: C, 63.7; H, 4.5; N, 8.3. Found: C, 63.8;H, 4.7; N, 8.0.

1-(8-Quinolylmethyl)imidazo[1,2-a]pyridinium bromide (49% yield), m.p.228°-230° C.

Anal. Calc'd for C₁₇ H₁₄ N₃ Br: C, 60.0; H, 4.2; N, 12.4. Found: C,59.7; H, 4.2; N, 12.0.

1-(2-Furfuryl)imidazo[1,2-a]pyridinium chloride (21% yield), m.p.170°-174° C.

Anal. Calc'd for C₁₂ H₁₁ ON₂ Cl.1/4H₂ O: C, 60.0; H, 5.3; N, 11.7.Found: C, 60.2; H, 4.9; N, 11.7.

1-(2-Phenethyl)imidazo[1,2-a]pyridinium bromide (61% yield), m.p.170°-172.5° C.

Anal. Calc'd for C₁₅ H₁₅ N₂ Br: C, 59.4; H, 5.0; N, 9.3. Found: C, 59.5;H, 5.1; N, 9.1.

EXAMPLE 3

Employing the procedure of Example 1-B, and starting withimidazo[1,2-a]pyridine and the appropriate halide, the followingquaternary salts are synthesized:

1-(2,3-dichlorobenzyl)imidazo[1,2-a]pyridinium chloride;1-(3,5-dichlorobenzyl)imidazo[1,2-a]pyridinium chloride;1-(3,4-dichlorobenzyl)imidazo[1,2-a]pyridinium bromide;1-(2-methoxybenzyl)imidazo[1,2-a]pyridinium bromide;1-(3-methoxybenzyl)imidazo[1,2-a]pyridinium chloride;1-(3-cyanobenzyl)imidazo[1,2-a]pyridinium iodide;1-(3-bromobenzyl)imidazo[1,2-a]pyridinium bromide;1-(3-fluorobenzyl)imidazo[1,2-a]pyridinium bromide;1-(3-phenylbenzyl)imidazo[1,2-a]pyridinium chloride;1-(3-sulfamoylbenzyl)imidazo[1,2-a]pyridinium chloride;1-(2-methylsulfonylbenzyl)imidazo[1,2-a]pyridinium chloride;1-(4-trifluoromethylbenzyl)imidazo[1,2-a]pyridinium bromide; and1-(3-furfuryl)imidazo[1,2-a]pyridinium bromide.

EXAMPLE 4 1-Benzyl-2,3-dihydro-1H-imidazo[1,2-a]pyridinium bromide A.2,3-dihydroimidazo[1,2-a]pyridine

A mixture of 72.5 g. of 2-aminopyridine and 67.0 g. of 2-chloroethanolis heated at 110° for 52 hrs. The mixture is cooled to room temperatureand is then treated with water and sufficient solid sodium carbonate togive pH 8. Chloroform (200 ml.) is added and the two-phase system heateduntil a solution results. The aqueous layer is separated, washed againwith chloroform (2×100 ml.) and subsequently concentrated to dryness.The residue from the aqueous layer is extracted with ethanol. Theinsolubles are filtered and the ethanol filtrate is allowed to stand atroom temperature overnight. The precipitated solids, comprising 30.5 g.of the product, 1-(2-hydroxyethyl)-2-aminopyridinium chloride arefiltered. Evaporation of the filtrate to half volume provides anadditional 31.4 g. of the desired material, m.p. 146°-149° C.

Fifty grams of the above-mentioned 1-(2-hydroxyethyl)-2-aminopyridiniumchloride is converted into 41.0 g., m.p. 178°-180° C., of the desiredproduct as the hydrobromide salt following the procedure of Burton, etal., J. Chem. Soc. (Perkins), (1972), 1940.

Sixteen grams of the hydrobromide salt in 100 ml. of water is treatedwith 20 ml. of 20% (w/v) aqueous sodium hydroxide solution. Theresulting solution is concentrated in vacuo to a low volume andextracted with benzene. The benzene layer is separated, dried oversodium sulfate and concentrated to 8.75 g. of a yellow oil whichcrystallizes to a low melting solid.

B. 1-benzyl-2,3-dihydro-1H-imidazo[1,2-a]pyridinium bromide

To 2.0 g. of 2,3-dihydroimidazo[1,2-a]pyridine in 40 ml. of dryacetonitrile is added 3.42 g. of α-bromotoluene and the resultingmixture heated to reflux overnight. The solution is cooled to roomtemperature and treated with 30 ml. of diethyl ether. The precipitatedsolid is filtered and recrystallized from acetonitrile, 1.64 g., m.p.143°-145° C.

Anal. Calc'd for C₁₄ H₁₅ N₂ Br: C, 57.8; H, 5.2; N, 9.6. Found: C, 57.6;H, 5.0; N, 9.6.

EXAMPLE 5

Starting with 2,3-dihydroimidazo[1,2-a]pyridine and the requisitehalide, and employing the procedure of Example 4-B, the followingcompounds are prepared:

1-(3-chlorobenzyl)-2,3-dihydro-1H-imidazo[1,2-a]pyridinium chloride,m.p. 173°-176° C.

Anal. Calc'd for C₁₄ H₁₄ N₂ Cl₂ : C, 59.8; H, 5.0; N, 10.0. Found: C,59.7; H, 5.1; N, 9.9.

1-(2,4-dichlorobenzyl)-2,3-dihydro-1H-imidazo[1,2-a]pyridinium chloride,m.p. 227°-229° C.

Anal. Calc'd for C₁₄ H₁₃ N₂ Cl₃ : C, 53.3; H, 4.2; N, 8.9. Found: C,53.2; H, 4.1; N, 9.1.

1-(2,6-dichlorobenzyl)-2,3-dihydro-1H-imidazo[1,2-a]pyridinium chloride,m.p. 254°-256° C.

Anal. Calc'd for C₁₄ H₁₃ N₂ Cl₃ : C, 53.3; H, 4.2; N, 8.9. Found: C,53.0; H, 4.3; N, 9.0.

1-(2-chlorobenzyl)-2,3-dihydro-1H-imidazo[1,2-a]pyridinium chloride,m.p. 258°-261° C.

Anal. Calc'd for C₁₄ H₁₄ N₂ Cl₂ : C, 59.8; H, 5.0; N, 10.0. Found: C,59.7; H, 5.0; N, 10.0.

1-(4-chlorobenzyl)-2,3-dihydro-1H-imidazo[1,2-a]pyridinium chloridehemihydrate, m.p. 181°-183° C.

Anal. Calc'd for C₁₄ H₁₄ N₂ Cl₂.1/2H₂ O: C, 57.9; H, 5.2; N, 9.7. Found:C, 57.6; H, 4.8; N, 9.6.

1-(4-methoxybenzyl)-2,3-dihydro-1H-imidazo[1,2-a]pyridinium chloridehemihydrate, m.p. 163°-165° C.

Anal. Calc'd for C₁₅ H₁₇ ON₂ Cl.1/2H₂ O: C, 63.1; H, 6.3; N, 9.8. Found:C, 62.8; H, 6.1; N, 9.9.

EXAMPLE 6

Employing the procedure of Example 4-B and starting with the2,3-dihydroimidazo[1,2-a]pyridine and the appropriate halide, thefollowing quaternary salts are synthesized:

    ______________________________________                                         ##STR7##                                                                 

    ______________________________________                                         R.sub.3                  X                                                   ______________________________________                                         ##STR8##                Cl                                                    ##STR9##                Br                                                    ##STR10##               Cl                                                    ##STR11##               Br                                                    ##STR12##               Cl                                                    ##STR13##               Br                                                    ##STR14##               Cl                                                    ##STR15##               Br                                                    ##STR16##               Br                                                    ##STR17##               Br                                                    ##STR18##               Br                                                    ##STR19##               Cl                                                    ##STR20##               Br                                                    ##STR21##               Br                                                    ##STR22##               Cl                                                    ##STR23##               Cl                                                    ##STR24##               Br                                                    ##STR25##               Cl                                                    ##STR26##               I                                                     ##STR27##               Br                                                    ##STR28##               Cl                                                    ##STR29##               Cl                                                    ##STR30##               Cl                                                    ##STR31##               Br                                                   and                                                                            R.sub. 2                 X                                                   ______________________________________                                         ##STR32##               Br                                                    ##STR33##               Cl                                                   ______________________________________                                    

EXAMPLE 7 1-Benzyl-6-chloroimidazo[1,2-a]pyridinium bromide

A solution of 2.3 g. of 6-chloroimidazo[1,2-a]pyridine and 3.42 g. ofα-bromotoluene in 40 ml. of dry acetonitrile is heated at refluxtemperatures overnight. The solution is cooled and 35 ml. of diethylether added. The precipitated solids are collected and twicerecrystallized from isopropanol-diethyl ether, 3.8 g., m.p. 193°-195° C.

Anal. Calc'd for C₁₄ H₁₂ N₂ ClBr: C, 52.0; H, 3.7; N, 8.7. Found: C,52.0; H, 3.8; N, 8.8.

EXAMPLE 8

The procedure of Example 7 is repeated, starting with the requisitereagents, to give the following quaternary salts:

1-(2-chlorobenzyl)-6-chloroimidazo[1,2-a]pyridinium chloride, m.p.242°-245° C.

Anal. Calc'd for C₁₄ H₁₁ N₂ Cl₃ : C, 53.6; H, 3.5; N, 8.9. Found: C,53.6; H, 3.6; N, 8.8.

1-(2,4-dichlorobenzyl)-6-chloroimidazo[1,2-a]pyridinium chloridemonohydrate, m.p. 90°-110° C.

Anal. Calc'd for C₁₄ H₁₀ N₂ Cl₄.H₂ O: C, 45.9; H, 3.3; N, 7.7. Found: C,45.7; H, 3.7; N, 7.2.

1-benzyl-8-benzyloxyimidazo[1,2-a]pyridinium bromide, m.p. 206°-209° C.

Anal. Calc'd for C₂₁ H₁₉ N₂ OBr: C, 63.8; H, 4.8; N, 7.1. Found: C,64.0; H, 4.8; N, 7.1.

1-(2-chlorobenzyl)-8-benzyloxyimidazo[1,2-a]pyridinium chloridehemihydrate, m.p. 209°-212° C.

Anal. Calc'd for C₂₁ H₁₈ ON₂ Cl₂.1/2 H₂ O: C, 64.0; H, 4.9; N, 7.1.Found: C, 63.8; H, 4.3; N, 7.0.

1-(2,4-dichlorobenzyl)-8-benzyloxyimidazo[1,2-a]pyridinium chloridemonohydrate, m.p. 216°-218° C.

Anal. Calc'd for C₂₁ H₁₇ ON₂ Cl₃ : C, 57.6; H, 4.4; N, 6.4. Found: C,57.4; H, 3.8; N, 6.3.

1-benzyl-5-chloroimidazo[1,2-a]pyridinium bromide, m.p. 223°-226° C.

Anal. Calc'd for C₁₄ H₁₂ N₂ BrCl: C, 52.0; H, 3.7; N, 8.7. Found: C,51.7; H, 3.7; N, 8.7.

1-(2-chlorobenzyl)-5-chloroimidazo[1,2-a]pyridinium chloride, m.p.191°-194° C.

Anal. Calc'd for C₁₄ H₁₁ N₂ Cl₃ : C, 53.6; H, 3.5; N, 8.9. Found: C,53.3; H, 3.5; N, 9.0.

1-(2,4-dichlorobenzyl)-5-chloroimidazo[1,2-a]pyridinium chloride, m.p.216°-218° C.

Anal. Calc'd for C₁₄ H₁₀ N₂ Cl₄ : C, 48.3; H, 2.9; N, 8.1. Found: C,48.3; H, 3.1; N, 8.0.

1-benzyl-5-benzyloxyimidazo[1,2-a]pyridinium bromide, m.p. 109°-115° C.

Anal. Calc'd for C₂₁ H₁₉ ON₂ Br: C, 63.8; H, 4.8; N, 7.1. Found: C,63.8; H, 4.9; N, 7.0.

1-benzyl-5-methoxyimidazo[1,2-a]pyridinium bromide, m.p. 95°-100° C.

Anal. Calc'd for C₁₅ H₁₅ ON₂ Br: C, 56.4; H, 4.7; N, 8.8. Found: C,56.8; H, 5.0; N, 9.0.

1-(2-chlorobenzyl)-5-methoxyimidazo[1,2-a]pyridinium chloride, m.p. 150°C.

Anal. Calc'd for C₁₅ H₁₄ ON₂ Cl₂ : C, 58.3; H, 4.6; N, 7.1. Found: C,58.2; H, 4.7; N, 9.3.

EXAMPLE 9

The procedure of Example 7 is repeated, starting with the appropriatesubstituted imidazo[1,2-a]pyridine and halide, to provide the followingquaternary salt:

    ______________________________________                                         ##STR34##                                                                    R.sub.1       R.sub.3            X                                            ______________________________________                                        6-Cl          2-FC.sub.6 H.sub.4 CH.sub.2                                                                      Cl                                           6-Cl          4-NCC.sub.6 H.sub.4 CH.sub.2                                                                     Cl                                           6-Cl          2-BrC.sub.6 H.sub.4 CH.sub.2                                                                     Br                                           8-φCH.sub.2 O                                                                           3,5-Cl.sub.2 C.sub.6 H.sub.3 CH.sub.2                                                            Cl                                           8-φCH.sub.2 O                                                                           3-BrC.sub.6 H.sub.4 CH.sub.2                                                                     Br                                           8-φCH.sub.2 O                                                                           3-CF.sub.3 C.sub.6 H.sub.4 CH.sub.2                                                              Cl                                           8-φCH.sub.2 O                                                                           4-φC.sub.6 H.sub.4 CH.sub.2                                                                  Br                                           5-CH.sub.3 O  3-CF.sub.3 C.sub.6 H.sub.4 CH.sub.2                                                              Cl                                           5-CH.sub.3 O  3-NCC.sub.6 H.sub.4 CH.sub.2                                                                     I                                            5-CH.sub.3 O  4-(CH.sub.3).sub.2 NSO.sub.2 C.sub.6 H.sub.4 CH.sub.2                                            Br                                           5-CH.sub.3 O  4-CH.sub. 3 OC.sub.6 H.sub.4 CH.sub.2                                                            Cl                                           5-φCH.sub.2 O                                                                           3-ClC.sub.6 H.sub.4 CH.sub.2                                                                     Cl                                           5-φCH.sub.2 O                                                                           4-BrC.sub.6 H.sub.4 CH.sub.2                                                                     Br                                           5-φCH.sub.2 O                                                                           3-CH.sub.3 OC.sub.6 H.sub.4 CH.sub.2                                                             Cl                                           5-φCH.sub.2 O                                                                           3,5-Cl.sub.2 C.sub.6 H.sub.3 CH.sub.2                                                            Cl                                           5-φCH.sub.2 O                                                                           4-FC.sub.6 H.sub.4 CH.sub.2                                                                      Br                                           7-Cl          C.sub.6 H.sub.5 CH.sub.2                                                                         Cl                                           7-Cl          2,4-Cl.sub.2 C.sub.6 H.sub.3 CH.sub.2                                                            Cl                                           7-Cl          3-BrC.sub.6 H.sub.4 CH.sub.2                                                                     Br                                           7-Cl          3-NCC.sub.6 H.sub.4 CH.sub.2                                                                     I                                            7-Cl          4-φC.sub.6 H.sub.4 CH.sub.2                                                                  Br                                           6-φCH.sub.2 O                                                                           2-FC.sub.6 H.sub.4 CH.sub.2                                                                      Cl                                           6-φCH.sub.2 O                                                                           2-BrC.sub.6 H.sub.4 CH.sub.2                                                                     Br                                           6-φCH.sub.2 O                                                                           3-φC.sub.6 H.sub.4 CH.sub.2                                                                  Cl                                           6-φCH.sub.2 O                                                                           β-naphthylmethyl-                                                                           Br                                           ______________________________________                                    

EXAMPLE 101-(2,4-Dichlorobenzyl)-2,3-dihydro-1H-6,8-dichloroimidazo[1,2-a]pyridiniumchloride

A mixture of 1.89 g. of 2,3-dihydro-6,8-dichloroimidazo[1,2-a]pyridineand 4.89 g. of 2,4-dichlorobenzyl chloride in 75 ml. of dry acetonitrileis heated at reflux temperatures overnight. Diethyl ether (35 ml.) isadded to the cooled reaction mixture, and the resulting precipitatedsolids filtered and dried. The desired product is further purified byrecrystallization from acetonitrile.

EXAMPLE 11

Starting with the requisite dihydroimidazo[1,2-a]pyridine andappropriate halide, and employing the procedure of Example 10, thefollowing quaternary salts are prepared:

    ______________________________________                                         ##STR35##                                                                    R.sub.1       R.sub.3          X                                              ______________________________________                                        6-Cl          2-FC.sub.6 H.sub.4 CH.sub.2                                                                    Cl                                             6-Cl          2-BrC.sub.6 H.sub.4 CH.sub.2                                                                   Br                                             8-φCH.sub.2 O                                                                           3-BrC.sub.6 H.sub.4 CH.sub.2                                                                   Br                                             8-φCH.sub.2 O                                                                           4-φC.sub.6 H.sub.4 CH.sub.2                                                                Br                                             5-CH.sub.3 O  3-NCC.sub.6 H.sub.4 CH.sub.2                                                                   I                                              5-CH.sub.3 O  4-CH.sub.3 OC.sub.6 H.sub.4 CH.sub.2                                                           Cl                                             5-φCH.sub.2 O                                                                           3-CH.sub.3 OC.sub.6 H.sub.4 CH.sub.2                                                           Cl                                             5-φCH.sub.2 O                                                                           3,5-Cl.sub.2 C.sub.6 H.sub.3 CH.sub.2                                                          Cl                                             5-φCH.sub.2 O                                                                           4-FC.sub.6 H.sub.4 CH.sub.2                                                                    Br                                             7-Cl          C.sub.6 H.sub.5 CH.sub.2                                                                       Cl                                             7-Cl          3-BrC.sub.6 H.sub.4 CH.sub.2                                                                   Br                                             7-Cl          4-φC.sub.6 H.sub.4 CH.sub.2                                                                Br                                             6-φCH.sub.2 O                                                                           2-FC.sub.6 H.sub.4 CH.sub.2                                                                    Cl                                             6-φCH.sub.2 O                                                                           2-BrC.sub.6 H.sub.4 CH.sub.2                                                                   Br                                             6-φCH.sub.2 O                                                                           β-naphthylmethyl                                                                          Br                                             and                                                                           R.sub.1       R.sub.2          X                                              ______________________________________                                        5-Cl          8-quinolylmethyl Cl                                             7-Cl          3-furfuryl       Br                                             ______________________________________                                    

EXAMPLE 12 1-Methyl-2-(4-methoxyphenyl)imidazo[1,2-a]pyridinium iodideA. 2-(4-methoxyphenyl)imidazo[1,2-a]pyridine

A mixture of 25.2 g. of sodium bicarbonate, 12.3 g. of 2-aminopyridineand 30 g. of a α-bromo-p-methoxyacetophenone in 100 ml. of water and 550ml. of absolute ethanol is heated at reflux temperatures for 1.5 hrs.The reaction mixture is concentrated under reduced pressure to a yellowsolid, which is partitioned between chloroform and water. The organiclayer is separated, dried over sodium sulfate. Removal of the chloroformin vacuo leaves the crude intermediate as a yellow solid.Recrystallization from ethanol-water give 15.2 g. of the desiredmaterial, m.p. 131°-134° C.

B. 1-methyl-2-(4-methoxyphenyl)imidazo[1,2-a]pyridinium iodide

To 2.23 g. of 2-(4-methoxyphenyl)imidazo[1,2-a]pyridine in 50 ml. ofacetonitrile is added 2.84 g. of methyl iodide, and the resultingreaction mixture refluxed for 3 hrs. Additional methyl iodide (2 ml.) isadded and reflux continued for one hour. The solids which precipitate oncooling are filtered and partially dissolved in boiling isopropanol andfiltered. The isopropanol filtrate is cooled and treated with diethylether. The crystallized product is filtered and dried to give 1.03 g.,m.p. 194°-196° C.

Anal. Calc'd for C₁₅ H₁₅ N₂ OI: C, 49.2; H, 4.1; N, 7.7. Found: C, 48.9;H, 4.2; N, 7.7.

EXAMPLE 13

Employing the procedure of Example 12-B, and starting with theappropriate 2-phenylimidazo[1,2-a]pyridine and methyl halide, thefollowing compounds are synthesized:

1-methyl-2-(4-bromophenyl)imidazo[1,2-a]pyridinium iodide, m.p.237°-241° C.

Anal. Calc'd for C₁₄ H₁₂ N₂ BrI: C, 40.5; H, 2.9; N, 6.8. Found: C,40.5; H, 3.0; N, 6.8.

1-methyl-2-(4-tolyl)imidazo[1,2-a]pyridinium iodide, m.p. 218°-220° C.

Anal. Calc'd for C₁₅ H₁₅ N₂ I: C, 51.4; H, 4.3; N, 8.0. Found: C, 51.6;H, 4.3; N, 8.1.

1-methyl-2-(4-chlorophenyl)imidazo[1,2-a]pyridinium iodide, m.p.240°-243° C.

Anal. Calc'd for C₁₄ H₁₂ N₂ ClI: C, 45.4; H, 3.3; N, 7.6. Found: C,45.9; H, 3.4; N, 7.7.

1-methyl-2-(2,4-dichlorophenyl)imidazo[1,2-a]pyridinium iodide, m.p.233°-234° C.

Anal. Calc'd for C₁₄ H₁₁ N₂ Cl₂ I: C, 41.5; H, 2.7; N, 6.9. Found: C,41.6; H, 2.8; N, 6.7.

EXAMPLE 14 1-Benzylimidazo[1,5-a]pyridinium bromide A.2-formamidomethylpyridine

A mixture of 32.4 g. of 2-aminomethylpyridine and 96 ml. of 97% formicacid is heated under reflux for 3.5 hrs. The resulting solution issubjected to vacuum distillation, the desired product being isolated asthe fraction boiling at 120° C./0.03 mm, 37.3 g. The product which isisolated as a yellow oil crystallized to a solid having a melting pointat about room temperature.

B. imidazo[1,5-a]pyridine

To 13.6 g. of 2-formamidomethylpyridine in a round-bottom flask is added25 ml. of phosphorous oxychloride. Following the exothermic reaction,the reaction mixture is cooled to room temperature, and quenched oncrushed ice. The aqueous mixture is treated with sufficient 20% aqueoussodium hydroxide solution to provide a pH of 9-10, and the liberatedproduct extracted into chloroform (3×300 ml.). The extracts arecombined, dried over sodium sulfate and concentrated to a light brownoil, 14.0 g.

C. 1-benzylimidazo[1,5-a]pyridinium bromide

Imidazo[1,5-a]pyridine (3.9 g.) in 100 ml. of dry acetonitrile istreated with 6.8 g. of α-bromotoluene, and the resulting reactionmixture heated under reflux for 3 hrs. The solution is cooled anddiluted with 250 ml. of diethyl ether. The resulting precipitate isfiltered and recrystallized from isopropanol-diethyl ether, 7.92 g.,m.p. 172°-176° C.

Anal. Calc'd for C₁₄ H₁₃ N₂ Br: C, 58.2; H, 4.5; N, 9.7. Found: C, 58.3;H, 4.7; N, 9.7.

EXAMPLE 15

The procedure of Example 14-C is repeated, starting with the appropriatehalide and imidazo[1,5-a]pyridine, to provide the indicated quaternarycompounds:

2-(2-chlorobenzyl)imidazo[1,5-a]pyridinium chloride, m.p. 153°-155° C.

Anal. Calc'd for C₁₄ H₁₂ N₂ Cl₂ : C, 60.2; H, 4.3; N, 10.0. Found: C,60.0; H, 4.6; N, 9.7.

2-(2,4-dichlorobenzyl)imidazo[1,5-a]pyridinium chloride hydrate, m.p.202°-207° C.

Anal. Calc'd for C₁₄ H₁₁ N₂ Cl₃.1/4 H₂ O: C, 52.9; H, 3.6; N, 8.8.Found: C, 53.0; H, 3.8; N, 8.6.

2-methylimidazo[1,5-a]pyridinium iodide, m.p. 160° C.

Anal. Calc'd for C₈ H₉ N₂ I: C, 36.9; H, 3.5; N, 10.8. Found: C, 37.1;H, 3.6; N, 10.9.

1-phenyl-2-methylimidazo[1,5-a]pyridinium iodide acetonitrile solvate,m.p. 84°-95° C.

Anal. Calc'd for C₁₄ H₁₃ N₂ I.CH₃ CN: C, 51.0; H, 4.3; N, 11.1. Found:C, 50.9; H, 4.4; N, 10.7.

2-methyl-3-phenylimidazo[1,5-a]pyridinium iodide, m.p. 197°-199° C.

Anal. Calc'd for C₁₄ H₁₃ N₂ I: C, 50.0; H, 3.9; N, 8.3. Found: C, 50.1;H, 4.0; N, 8.3.

2-benzylimidazo[1,5-a]quinolinium bromide, m.p. 224°-226° C.

Anal. Calc'd for C₁₈ H₁₅ N₂ Br: C, 63.7; H, 4.5; N, 8.3. Found: C, 63.4;H, 4.8; N, 8.2.

2-(2-chlorobenzyl)imidazo[1,5-a]quinolinium chloride, m.p. 223°-225° C.

Anal. Calc'd for C₁₈ H₁₄ N₂ Cl₂ : C, 65.7; H, 4.3; N, 8.5. Found: C,65.3; H, 4.2; N, 8.8.

2-(2,4-dichlorobenzyl)imidazo[1,5-a]quinolinium chloride, m.p. 263°-266°C.

Anal. Calc'd for C₁₈ H₁₃ N₂ Cl₃ : C, 59.5; H, 3.6; N, 7.7. Found: C,59.3; H, 3.9; N, 7.8.

EXAMPLE 16

The process of Example 14-C is again repeated employing as startingreagents the requisite halide and imidazo[1,5-a]pyridine or -quinoline,to provide the following products:

    ______________________________________                                         ##STR36##                                                                    R.sub.4           R.sub.5  R.sub.6  X                                         ______________________________________                                        4-ClC.sub.6 H.sub.4 CH.sub.2                                                                    H        H        Cl                                        3,4-Cl.sub.2 C.sub.6 H.sub.3 CH.sub.2                                                           H        H        Cl                                        2,6-Cl.sub.2 C.sub.6 H.sub.3 CH.sub.2                                                           H        H        Cl                                        C.sub.2 H.sub.5   H        φ    I                                         n-C.sub.3 H.sub.7 H        φ    Br                                        C.sub.2 H.sub.5   φ    H        I                                         i-C.sub.3 H.sub.7 φ    H        I                                         C.sub.6 H.sub.5 CH.sub.2                                                                        φ    H        Br                                        4-ClC.sub.6 H.sub.4 CH.sub.2                                                                    φ    H        Cl                                        3,5-Cl.sub.2 C.sub.6 H.sub.3 CH.sub.2                                                           φ    H        Cl                                        2,4-Cl.sub.2 C.sub.6 H.sub.3 CH.sub.2                                                           φ    H        Cl                                        2-ClC.sub.6 H.sub.4 CH.sub.2                                                                    φ    H        Cl                                        2-ClC.sub.6 H.sub.4 CH.sub.2                                                                    H        φ    Cl                                        3,4-Cl.sub.2 C.sub.6 H.sub.3 CH.sub.2                                                           H        φ    Cl                                        C.sub.6 H.sub.5 CH.sub.2                                                                        H        φ    Br                                        3-ClC.sub.6 H.sub.4 CH.sub.2                                                                    H        φ    Cl                                        ______________________________________                                        and                                                                            ##STR37##                                                                    R.sub.4           R.sub.5  R.sub.6  X                                         ______________________________________                                        4-ClC.sub.6 H.sub.4 CH.sub.2                                                                    H        H        Cl                                        2,6-Cl.sub.2 C.sub.6 H.sub.3 CH.sub.2                                                           H        H        Cl                                        3,5-Cl.sub.2 C.sub.6 H.sub.3 CH.sub.2                                                           H        H        Cl                                        CH.sub.3          φ    H        I                                         C.sub.2 H.sub.5   φ    H        Br                                        i-C.sub.3 H.sub.7 φ    H        Br                                        C.sub.6 H.sub.5 CH.sub.2                                                                        φ    H        Cl                                        4-ClC.sub.6 H.sub.4 CH.sub.2                                                                    φ    H        Cl                                        2,4-Cl.sub.2 C.sub.6 H.sub.3 CH.sub.2                                                           φ    H        Cl                                        CH.sub.3          H        φ    i                                         n-C.sub.C.sub.3 H.sub.7                                                                         H        φ    Br                                        C.sub.6 H.sub.5 CH.sub.2                                                                        H        φ    Br                                        3-ClC.sub.6 H.sub.4 CH.sub.2                                                                    H        φ    Cl                                        4-ClC.sub. 6 H.sub.4 CH.sub.2                                                                   H        φ    Cl                                        3,5-Cl.sub.2 C.sub.6 H.sub.3 CH.sub.2                                                           H        φ    Cl                                        ______________________________________                                    

EXAMPLE 17 1-Benzyl-1H-imidazo[2,1-a]isoquinolinium bromide

A solution of 600 mg. of imidazo[2,1-a]isoquinoline and 610 mg. ofα-bromotoluene in 25 ml. of acetonitrile is heated under reflux for twodays. The reaction mixture is subsequently cooled and diluted withdiethyl ether. The resulting precipitate is recrystallized fromisopropanol-diethyl ether and then twice from isopropanol to give 570mg., m.p. 247°-249° C.

Anal. Calc'd for C₁₈ H₁₅ N₂ Br: C, 63.7; H, 4.5; N, 8.3. Found: C, 63.6;H, 4.8; N, 8.3.

Similarly is prepared:

1-(2-chlorobenzyl)-1H-imidazo[2,1-a]isoquinolinium chloride hydrate,m.p. 226°-229° C.

Anal. Calc'd for C₁₈ H₁₄ N₂ Cl₂ ·H₂ O: C, 62.3; H, 4.6; N, 8.1. Found:C, 62.0; H, 4.8; N, 8.0.

EXAMPLE 18 2-Benzylimidazo[5,1-a]isoquinolinium bromide

Following the general procedure of Example 17, 1.68 g. ofimidazo[5,1-a]isoquinoline and 2.05 g. of α-bromotoluene in 50 ml. ofacetonitrile is heated at reflux temperature overnight. Diethyl ether(25 ml.) is added to the cooled reaction mixture and the resultingsolids filtered. Recrystallization from isopropanol-diethyl etherprovides 2.7 g. of the purified product, m.p. 231°-234° C.

Anal. Calc'd for C₁₈ H₁₅ N₂ Br: C, 63.7; H, 4.5; N, 8.3. Found: C, 63.6;H, 4.6; N, 8.1.

Similarly are prepared:

2-(2-chlorobenzyl)imidazo[5,1-a]isoquinolinium chloride hydrate, m.p.215°-217° C.

Anal. Calc'd for C₁₈ H₁₄ N₂ Cl₂ ·1/4 H₂ O: C, 64.6; H, 4.4; N, 8.4.Found: C, 64.4; H, 4.4; N, 8.2.

2-(2,4-dichlorobenzyl)imidazo[5,1-a]isoquinolinium chloride hydrate,m.p. 258°-261° C.

Anal. Calc'd for C₁₈ H₁₃ N₂ Cl₃ ·1/4 H₂ O: C, 58.7; H, 3.8; N, 7.6.Found: C, 58.8; H, 3.8; N, 7.5.

EXAMPLE 19 1-Benzylpyrazolo[1,5-a]pyridinium bromide

Pyrazolo[1,5-a]pyridine (1.0 g.) and 2.05 g. of α-bromotoluene in 30 ml.of acetonitrile are heated under reflux overnight. The reaction mixtureis cooled and diluted with 50 ml. of diethyl ether. The oil whichinitially separated from solution crystallizes on stirring, and issubsequently recrystallized from isopropanol-diethyl ether, 1.3 g. m.p.135°-138° C.

Anal. Calc'd for C₁₄ H₁₃ N₂ Br: C, 58.2; H, 4.5; N, 9.7. Found: C, 58.3;H, 4.6; N, 9.6.

Similarly are prepared:

1-(2-chlorobenzyl)pyrazolo[1,5-a]pyridinium chloride hydrate, m.p.121°-123° C.

Anal. Calc'd for C₁₄ H₁₂ N₂ Cl₂ ·H₂ O: C, 56.6; H, 4.8; N, 9.4. Found:C, 55.9; H, 4.6; N, 9.3.

1-(2,4-dichlorobenzyl)pyrazolo[1,5-a]pyridinium chloride hydrate, m.p.125°-130° C.

Anal. Calc'd for C₁₄ H₁₁ N₂ Cl₃ ·H₂ O: C, 50.7; H, 4.0; N, 8.5. Found:C, 50.8; H, 4.0; N, 8.4.

EXAMPLE 20 2-Benzylpyrrolo[1,2-a]pyrazinium bromide

A reaction mixture comprising 2.0 g. of pyrrolo[1,2-a]pyrazine and 4.27g. of α-bromotoluene in 50 ml. of dry acetonitrile is stirred at roomtemperature overnight. Diethyl ether (50 ml.) is added to the suspensionand the solids filtered. Recrystallization from isopropanol-diethylether gives 3.48 g. of the purified product, m.p. 173°-177° C.

Anal. Calc'd for C₁₄ H₁₃ N₂ Br: C, 58.2; H, 4.5; N, 9.7. Found: C, 58.0;H, 4.6; N, 9.6.

Similarly are prepared:

2-(2-chlorobenzyl)pyrrolo[1,2-a]pyrazinium chloride hydrate, m.p.188°-190° C.

Anal. Calc'd for C₁₄ H₁₂ N₂ Cl₂ ·1/2 H₂ O: C, 58.4; H, 4.6; N, 9.7.Found: C, 58.6; H, 4.6; N, 9.7.

2-(2,4-dichlorobenzyl)pyrrolo[1,2-a]pyrazinium chloride hydrate, m.p.208°-211° C.

Anal. Calc'd for C₁₄ H₁₁ N₂ Cl₃ ·1/4 H₂ O: C, 52.9; H, 3.6; N, 8.8.Found: C, 52.7; H, 3.7; N, 8.7.

5-benzylpyrrolo[1,2-a]quinoxalinium bromide hydrate, m.p. 204°-206° C.

Anal. Calc'd for C₁₈ H₁₅ N₂ Br·H₂ O: C, 60.5; H, 4.8; N, 7.8. Found: C,60.9; H, 4.7; N, 7.8.

5-(2-chlorobenzyl)pyrrolo[1,2-a]quinoxalinium chloride hydrate, m.p.228° C. (dec.).

Anal. Calc'd for C₁₈ H₁₄ N₂ Cl₂ ·1/4 H₂ O: C, 64.8; H, 4.4; N, 8.4.Found: C, 64.9; H, 4.4; N, 8.2.

5-(4-chlorobenzyl)pyrrolo[1,2-a]quinoxalinium chloride hydrate, m.p.215° C. (dec.).

Anal. Calc'd for C₁₈ H₁₄ N₂ Cl₂ ·3/4 H₂ O: C, 63.1; H, 4.6; N, 8.2.Found: C, 63.1; H, 4.5; N, 8.0.

EXAMPLE 21

Following the procedure of Example 20, and starting with the appropriatehalide and heterocyclic base, the indicated quaternary compounds areprepared:

5-(2,4-dichlorobenzyl)pyrrolo[1,2-a]quinoxalinium chloride;2-(4-chlorobenzyl)pyrrolo[1,2-a]pyrazinium chloride;1-(4-chlorobenzyl)pyrazolo[1,5-a]pyridinium bromide;1-(2,4-dichlorobenzyl)-1H-imidazo[2,1-a]isoquinolinium chloride;1-(4-chlorobenzyl)-1H-imidazo[2,1-a]isoquinolinium bromide; and2-(4-chlorobenzyl)imidazo[5,1-a]isoquinolinium bromide.

EXAMPLE 22 1-Benzylimidazo[1,2-a]pyridinium Salts

An ion exchange column approximately 1"×24" is packed with Amberlite 1R400 in 2 N aqueous sodium hydroxide solution. The column is thoroughlywashed successively with 3 l. of 1 N aqueous sodium hydroxide, 3 l. 5 Naqueous sodium hydroxide, 2 l. 2.5 N aqueous sodium hydroxide, and 3 l.5 N aqueous sodium hydroxide. The column is then washed with dionizedwater until the washings are neutral to pH paper.

Acetate Salt

One gram of 1-benzylimidazo[1,2-a]pyridinium bromide dissolved in wateris passed through the prepared column. Deonized water is then passedthrough the column until all basic fractions (via pH paper) have beencollected. To the combined basic fractions is added 10 ml. of aceticacid and the resulting solution concentrated to dryness in vacuo. Theresulting oil crystallizes when triturated with isopropanol-ethylacetate. The acetate salt is very hydroscopic.

Sulfate Salt

As in the description for the preparation of the acetate salt, 1 g. of1-benzylimidazo[1,2-a]pyridinium bromide dissolved in water is passedthrough the aforementioned prepared column, the basic fractionsresulting from the dionized water washes being collected (50 ml.). Tothese combined basic fractions is added 170 mg. of sulfuric acid and theresulting solution concentrated under reduced pressure to dryness, 680mg., m.p. 257° C.

Anal. Calc'd for C₂₈ H₂₆ N₄ O₄ S: C, 65.4; H, 5.1; N, 10.9. Found: C,65.3; H, 5.0; N, 10.5.

Iodide Salt

Employing the same general procedure, 850 mg. of1-benzylimidazo[1,2-a]pyridinium bromide gave 870 mg. of thecorresponding iodide salt, m.p. 134°-136° C.

Anal. Calc'd for C₁₄ H₁₃ N₂ I: C, 50.0; H, 3.9; N, 8.3. Found: C, 49.9;H, 3.9; N, 8.1.

Tosylate Salt

Employing the same procedure, 850 mg. of 1-benzylimidazo[1,2-a]pyridinium bromide gave 850 mg. of the corresponding tosylatesalt, m.p. 156°-158° C.

Anal. Calc'd for C₂₁ H₂₀ O₃ N₂ S: C, 66.3; H, 5.3; N, 7.4. Found: C,65.9; H, 5.3; N, 7.4.

EXAMPLE 23 Hypoglycemic Testing

The hypoglycemic testing of the compounds of the present invention iscarried out by a standard procedure, and comprises grouping eight,Hartley strain, male guinea pigs which have been fasted 18-24 hrs. ineach group. Blood samples are obtained from thepentobarbital-anesthetized animals by cardiac puncture. Each of theeight animals is dosed i.p. with a given dose of the test compound.Blood samples are taken 1, 2, and 4 hours following the dozing, and thevenous blood diluted 1:10 with saline and assayed for blood sugar levelson an Auto-Analyzer, the levels being expressed as mg.%. The activityfor the test compound is expressed as the percent lowering of the bloodsugar at the 1, 2, and 4 hr. when compared with the blood sugar level ofa group of eight control animals which have been similarly dosed with asaline solution.

The following representative quaternary salts were tested ashypoglycemic agents following the above mentioned procedure, and foundto be active at the indicated dose level.

    ______________________________________                                         ##STR38##                                                                                             % Fall Blood                                                           Dose   Sugar Level                                          R.sub.1 R.sub.3       X     mg./kg.                                                                              T.sub.1                                                                            T.sub.2                                                                            T.sub.4                          ______________________________________                                        H       C.sub.6 H.sub.5 CH.sub.2                                                                    I     30     18   55   65                               H       2-ClC.sub.6 H.sub.4 CH.sub.2                                                                Cl    25     14   27   57                               H       2,6-Cl.sub.2 C.sub.6 H.sub.3 CH.sub.2                                                       Cl    50      4   16   49                               H       4-CH.sub.3 OC.sub.6 H.sub.4 CH.sub.2                                                        Cl    50     19   51   60                               H       4-FC.sub.6 H.sub.4 CH.sub.2                                                                 Br    50     33   70   89                               H       4-BrC.sub.6 H.sub.4 CH.sub.2                                                                Br    50     51   84   --                               H       3-CF.sub.3 C.sub.6 H.sub.4 CH.sub.2                                                         Cl    50     10   25   80                               H       4-φC.sub.6 H.sub.5 CH.sub.2                                                             Br    50     45   53   46                               H       C.sub.6 H.sub.5 CH.sub.2 CH.sub.2                                                           Br    50     37   75   80                               5-CH.sub.3 O                                                                          C.sub.6 H.sub.5 CH.sub.2                                                                    Br    50     31   70   86                               8-φCH.sub.2 O                                                                     2-ClC.sub.6 H.sub.4 CH.sub.2                                                                Cl    50     17   70   --                               6-Cl    2-ClC.sub.6 H.sub.4 CH.sub.2                                                                Cl    50      5   32   35                               and                                                                           R.sub.1 R.sub.2                                                               ______________________________________                                        H       2-furfuryl-   Cl    50     38   71   67                               H       8-quinolylmethyl-                                                                           Br    50     14   68   86                               ______________________________________                                    

    ______________________________________                                         ##STR39##                                                                                              % Fall                                                                        Blood Sugar                                                            Dose,  Level                                               R.sub.4      R.sub.5                                                                              R.sub.6                                                                              X   mg./kg.                                                                              T.sub.1                                                                           T.sub.2                                                                           T.sub.4                         ______________________________________                                        C.sub.6 H.sub.5 CH.sub.2                                                                   H      H      Br  18     17  63  72                              2,4-Cl.sub.2 C.sub.6 H.sub.3 CH.sub.2                                                      H      H      Cl  25      7  14  28                              2-ClC.sub.6 H.sub.4 CH.sub.2                                                               H      H      Cl  18     13  41  67                              ______________________________________                                    

    ______________________________________                                         ##STR40##                                                                                        Dose,   % Fall Blood Sugar Level                          Q    Z      X       mg./kg. T.sub.1                                                                              T.sub.2                                                                              T.sub.4                             ______________________________________                                        H    H      Br      50      21     25     80                                  Cl   Cl     Cl      50       0      3     20                                  ______________________________________                                         ##STR41##                                                                                        Dose,   % Fall Blood Sugar Level                          Q    Z      X       mg./kg. T.sub.1                                                                              T.sub.2                                                                              T.sub.4                             ______________________________________                                        Cl   H      Cl      18       7     13     14                                  H    H      Br      50      31     59     86                                  ______________________________________                                    

    ______________________________________                                         ##STR42##                                                                                        Dose,   % Fall Blood SugarLevel                           Q    Z      X       mg./kg. T.sub.1                                                                              T.sub.2                                                                              T.sub.4                             ______________________________________                                        H    H      Br      50      18     62     86                                  ______________________________________                                         ##STR43##                                                                                        Dose,   % Fall Blood Sugar Level                          Q    Z      X       mg./kg. T.sub.1                                                                              T.sub.2                                                                              T.sub.4                             ______________________________________                                        Cl   Cl     Cl      50       9     21     46                                  H    H      Br      50      10     62     64                                  Cl   H      Cl      50      13     33     31                                  ______________________________________                                    

    ______________________________________                                         ##STR44##                                                                                         % Fall Blood                                                          Dose,   Sugar Level                                              Z     Y        X       mg./kg. T.sub.1                                                                             T.sub.2                                                                             T.sub.4                            ______________________________________                                        Cl    Cl       I       50       0    16    43                                 H     Cl       I       50      18    68    90                                 H     Br       I       50      14    53    70                                 H     CH.sub.3 O                                                                             I       50      23    53    52                                 H     H        Br      18       8    32    78                                  ##STR45##     18         4      13    40                                     ______________________________________                                    

EXAMPLE 24 HypoglycemicActivity--1-benzyl-2-methylimidazo[1,2-a]pyridinium bromide vs.1-benzylimidazo[1,2-a]pyridinium bromide

The known compound, 1-benzyl-2-methylimidazo[1,2-a]pyridinium bromide,reported by Bradsher, et. al., J. Heterocyclic Chem., 2, 331 (1965), iscompared with the desmethyl homolog of the present invention by thehypoglycemic testing procedure of Example 23. The results are asfollows:

    ______________________________________                                               % Fall-Blood Sugar                                                            level                                                                          ##STR46##                                                                                   ##STR47##                                               Dose,                                                                         mg./kg.  T.sub.1 T.sub.2 T.sub.4                                                                             T.sub.1                                                                             T.sub.2                                                                             T.sub.4                            ______________________________________                                        18        2       5       0     9    39    60                                 25        4      14      40    15    49    80                                 50       21      52      63    40    84     90*                               ______________________________________                                         *only one animal surviving                                               

The results indicate that the 1-benzylimidazo[1,2-a]pyridinium of thepresent invention is superior to the known compound in hypoglycemicactivity. It is further noted that while the compound of the instantinvention is active at 18 mg./kg., the hypolycemic activity of1-benzyl-2-methylimidazo[1,2-a]pyridinium bromide is indistinguishablefrom the control group.

PREPARATION A I. Imidazo[1,2-a]pyridines a. Imidazo[1,2-a]pyridine

A mixture of 47 g. of 2-aminopyridine, 120 g. of 45% chloroacetaldehydesolution in water and 50.4 g. of sodium bicarbonate in 400 ml. ofanhydrous ethanol and 100 ml. of water is heated to reflux for 3 hrs.The reaction mixture is cooled, treated with 900 ml. of water andextracted with diethyl ether (3×700 ml.). The combined extracts aredried over sodium sulfate and concentrated to a brown oil. Distillationgives 18.8 g. of the desired intermediate as a light yellow oil, b.p.70° C./0.02 mm.

b. Employing the general procedure of Preparation A-Ia and starting withthe appropriate aminopyridine and chloroacetaldehyde or an acetalthereof, the following intermediate imidazo[1,2-a]pyridines areprepared:

6-chloroimidazo[1,2-a]pyridine, 8-benzyloxyimidazo[1,2-a]pyridine,5-chloroimidazo[1,2-a]pyridine, 7-chloroimidazo[1,2-a]pyridine,5-methylimidazo[1,2-a]pyridine, 6-methylimidazo[1,2-a]pyridine,8-methylimidazo[1,2-a]pyridine and 6-benzyloxyimidazo[1,2-a]pyridine.

c. 5-Methoxyimidazo[1,2-a]pyridine

A mixture of 8.08 g. of 5-chloroimidazo[1,2-a]pyridine and 5.4 g. ofsodium methoxide in 100 ml. of dimethylformamide is allowed to stir atroom temperature overnight. The reaction mixture is poured on to 800 ml.of ice and water and extracted with chloroform (3×100 ml.). Thechloroform extracts are combined, dried over sodium sulfate andconcentrated to an oil. The oil is subsequently dissolved inethylacetate and treated with sufficient hydrogen chloride in ethylacetate to completely convert to free base to the hydrochloride salt,which is filtered and dried, 8.0 g., m.p. 175°-177° C.

An aqueous solution of 5.55 g. of 5-methoxyimidazo[1,2-a]pyridinehydrochloride is made strongly basic by the addition of aqueous sodiumhydroxide. The cloudy solution is extracted with methylene chloride(4×75 ml.) and the extracts combined and dried over sodium sulfate.Removal of the solvent leaves 5-methoxyimidazole[1,2-a]pyridine as ayellow oil, 4.5 g.

d. Starting with the appropriate halo substituted imidazo[1,2-a]pyridineand alkoxide and employing the procedure of Preparation AI-c, thefollowing intermediates are synthesized;

5-benzyloxyimidazo[1,2-a]pyridine and 8-benzyloxyimidazo[1,2-a]pyridine.

e. 2,3-dihydroimidazo[1,2-a]pyridine

A mixture of 72.5 g. of 2-aminopyridine and 67.0 g. of 2-chloroethanolis heated at 110° for 52 hrs. The mixture is cooled to room temperatureand is then treated with water and sufficient solid sodium carbonate togive pH 8. Chloroform (200 ml.) is added and the two-phase system heateduntil a solution results. The aqueous layer is separated, washed againwith chloroform (2×100 ml.) and subsequently concentrated to dryness.The residue from the aqueous layer is extracted with ethanol. Theinsolubles are filtered and the ethanol filtrate is allowed to stand atroom temperature overnight. The precipitated solids, comprising 30.5 g.of the product, 1-(2-hydroxyethyl)-2-aminopyridinium chloride arefiltered. Evaporation of the filtrate to half volume provides anadditional 31.4 g. of the desired material, m.p. 146°-149° C.

Fifty grams of the above-mentioned 1-(2-hydroxyethyl)-2-aminopyridiniumchloride is converted into 41.0 g., m.p. 178°-180° C., of the desiredproduct as the hydrobromide salt following the procedure of Burton, etal., J. Chem. Soc. (Perkins), (1972), 1940.

Sixteen grams of the hydrobromide salt in 100 ml. of water is treatedwith 20 ml. of 20% (w/v) aqueous sodium hydroxide solution. Theresulting solution is concentrated in vacuo to a low volume andextracted with benzene. The benzene layer is separated, dried oversodium sulfate and concentrated to 8.75 g. of a yellow oil whichcrystallizes to a low melting solid.

f. Following the procedure of Preparation AI-e and starting with theappropriate aminopyridine, the indicated intermediate2,3-dihydroimidazo[1,2-a]pyridine compounds are prepared:

6-chloro-2,3-dihydroimidazo[1,2-a]pyridine,8-benzyloxy-2,3-dihydroimidazo[1,2-a]pyridine,5-chloro-2,3-dihydroimidazo[1,2-a]pyridine,5-methoxy-2,3-dihydroimidazo[1,2-a]pyridine,5-benzyloxy-2,3-dihydroimidazo[1,2-a]pyridine and7-chloro-2,3-dihydroimidazo[1,2-a]pyridine

g. 2-(2,4-dichlorophenyl)imidazo[1,2-a]pyridine

A reaction mixture comprising 25.2 g of sodium bicarbonate, 18.84 g. of2-aminopyridine and 44.7 g. of 2,2',4-trichloroacetophenone in 100 ml.of water and 550 ml. of ethanol is heated to reflux for 18 hrs. Themixture is cooled and concentrated under reduced pressure to a mixtureof crystals and an oil. The residual material is partitioned betweenwater and chloroform, and the water layer subsequently separated andwashed with fresh chloroform (2×100 ml.). All the chloroform extractsare combined, dried over sodium sulfate and concentrated in vacuo. Theresidue is taken up in a minimum amount of ethyl acetate from which itcrystallizes on standing, 1.245 g., m.p. 174°-177° C.

h. Starting with the requisite acetophenone and 2-aminopyridine andrepeating the procedure of Preparation AI-g, the following intermediate2-Arylimidazo[1,2-a]pyridines are prepared:

2-(4-methoxyphenyl)imidazo[1,2-a]pyridine,2-(4-bromophenyl)imidazo[1,2-a]pyridine,2-(4-tolyl)imidazo[1,2-a]pyridine, and2-(4-chlorophenyl)imidazo[1,2-a]pyridine.

II. Imidazo[1,5-a]pyridines a. Imidazo[1,5-a]pyridine

A mixture of 32.4 g. of 2-aminomethylpyridine and 96 ml. of 97% formicacid is heated under reflux for 3.5 hrs. The resulting solution issubjected to vacuum distillation, the desired product,2-formamidomethylpyridine, being isolated as a yellow oil crystallizesto a solid having a melting point at about room temperature.

To 13.6 g. of 2-formamidomethylpyridine in a round-bottom flask is added25 ml. of phosphorous oxychloride. Following the exothermic reaction,the reaction mixture is cooled to room temperature, and quenched oncrushed ice. The aqueous mixture is treated with sufficient 20% aqueoussodium hydroxide solution to provide a pH of 9-10, and the liberatedproduct extracted into chloroform (3×300 ml.). The extracts arecombined, dried over sodium sulfate and concentrated to giveimidazo[1,5-a]pyridine as a light brown oil, 14.0 g.

b. The procedure of Preparation AII-a is repeated starting with theappropriate reagents to provide the following intermediates:

1-phenylimidazo[1,5-a]pyridine and 3-phenylimidazo[1,5-a]pyridine.

III. Imidazo[1,5-a]quinolines a. Imidazo[1,5-a]quinoline

A solution of 7.7 g of 2-cyanoquinoline in 100 ml. of acetic acid istreated with 500 mg. of 5% palladium-on-carbon, and the resultingmixture shaken in a hydrogen atmosphere at room temperature at aninitial pressure of 50 psi. When the theoretical amount of hydrogen hadbeen taken up, the catalyst is filtered and the filtrate concentrated invacuo to a brown oil. Water is added to the residue and rendered basicby the addition of 1N aqueous sodium hydroxide. The product,2-aminomethylquinoline, is extracted into benzene. The benzene extractsare combined, dried and concentrated to an oil, which is used withoutfurther purification.

Following the procedure of Preparation AIII-a, 7.92 g. of2-aminomethylquinoline is formylated with 50 ml. of 97% formic acid togive 5.97 g. of 2-formamidomethylquinoline, m.p. 108°-114° C.

Treatment of 1.86 g. of 2-formamidomethylquinoline with 15 ml. ofphosphorous oxychloride as in Preparation AIII-a gaveimidazo[1,5-a]quinoline, which is used without purification.

IV. Imidazo[5,1-a]isoquinolines a. Imidazo[5,1-a]isoquinoline

The procedure of Zimmer, et al., Tet. Letters, #24, 2805(1968), isemployed for the synthesis of this intermediate.

V. Pyrazolo[1,5-a]pyridines Pyrazolo[1,5-a]pyridine

The procedure of D. Dunham, Ph.D. Thesis, Ohio University, Athens, Ohio,is employed for the preparation of this intermediate.

VI. Pyrrolo[1,2-a]pyrazines a. Pyrrolo[1,2-a]pyrazine

The procedure of D. Dunham, Ph.D. Thesis, Ohio University, Athens, Ohio,is employed for the synthesis of this intermediate.

VII. Pyrrolo[1,2-a]quinoxalines a. Pyrrolo[1,2-a]quinoxaline

The procedure as taught by Cheeseman, et al., J. Chem. Soc., 852 (1966)is employed for the synthesis of this intermediate.

PREPARATION B I. Aralkyl Halides a. Benzyl halides

The benzyl halides employed as intermediates leading to the claimedcompounds are commercially available, or can be prepared by processes inthe chemical literature such as those taught by Wagner and Zook"Synthetic Organic Chemistry," John Wiley and Sons, New York, 1953, pp.88-147.

b. Heterocyclic Alkyl halides

These halide intermediates are commercial materials or are synthesizedby known preparatory procedures such as those taught in theaforementioned Wagner and Zook reference.

What is claimed is:
 1. A compound selected from the group consisting of:##STR48## wherein R is hydrogen or the carbon and hydrogen atomscompleting a fused 6,7-benzo moiety; R₄ is selected from the groupconsisting of alkyl having one to three carbon atoms, benzyl andsubstituted benzyl wherein said substituent is selected from the groupconsisting of chloro and dichloro; R₅ and R₆ are each selected from thegroup consisting of phenyl and hydrogen, provided that when R₅ and R₆are each hydrogen, R₄ is selected from the group consisting of benzyland substituted benzyl wherein said substituent is selected from thegroup consisting of chloro and dichloro; and X is a pharmaceuticallyacceptable anion.
 2. A compound of claim 1 wherein R is hydrogen and R₅and R₆ are each hydrogen.
 3. The compound of claim 2,2-(2-chlorobenzyl)imidazo[1,5-a]pyridinium chloride.
 4. The compound ofclaim 2, 2-benzylimidazo[1,5-a]pyridinium bromide.
 5. A compound ofclaim 1 wherein R₄ is methyl and R₅ is phenyl.
 6. The compound of claim5, 1-phenyl-2-methylimidazo[1,5-a]pyridinium iodide.
 7. A compound ofclaim 1 wherein R₄ is methyl and R₆ is phenyl.
 8. The compound of claim7, 2-methyl-3-phenylimidazo[1,5-a]pyridinium iodide.
 9. A compound ofclaim 1 wherein R is the carbon and hydrogen atoms completing a fused6,7-benzo moiety and R₅ and R₆ are each hydrogen.
 10. The compound ofclaim 9, 2-benzylimidazo[1,5-a]quinolinium bromide.
 11. The compound ofclaim 9, 2-(2-chlorobenzyl)imidazo[1,5-a]quinolinium chloride.